5.0.0-0 3.0 which macrophages sense M. tuberculosis infection to initiate the cytosolic surveillance pathway specific to M. tuberculosis may help in the development of new TB treatments and diagnostics. and diagnostics for a broad range of infectious diseases. bacterial infections, understanding its function may lead to the development of new treatments persistent infection. gain access to the cytosol. Ultimately, by understanding tuberculosis pathogenesis at the activated by the pathway work to protect the host from infection. The studies proposed here will molecular level, we hope to aid in the discovery of new therapies to combat and eradicate this and also identify the bacterial molecule(s) sensed by macrophages and determine how they early stages of M. tuberculosis infection. test this model and provide molecular details of host-pathogen interactions critical during the profiling work, we found that M. tuberculosis, a vacuolar pathogen, elicits cytosolic surveillance pathway by M. tuberculosis is important for host control and that into microbial players that modulate the host response. We hypothesize that activation of the depends completely on the bacterial ESX-1 secretion system, providing an unexpected window originates in the cytosol of infected macrophages. E Because cytosolic recognition by macrophages is conserved in many Specifically, we will determine the mechanism by Likewise, elucidating the responses genes Tuberculosis (TB) is a persistent lung infection that has plagued mankind for centuries and ranks as one of the most serious threats to world health today. The 2-3 million deaths attributed yearly to the disease, as well as the emergence of strains resistant to all of the available chemotherapeutic agents, urgently call for the development of new therapies to treat TB. Furthermore, the threat of drug-resistant TB as a bioterrorism agent has led to it's listing as a NIAID Category C Priority Pathogen for biodefense research. How the TB bacillus interacts with host cells in order to grow during infection is not well understood. The primary objective of the proposed research is to understand the mechanisms by which this pathogen triggers and manipulates host responses of its primary host cell, the macrophage. From our transcriptional an response that lmportanfly, elicitation of this response -3- -y, ti' 0.o vii -[unreadable]a aim (gyp Q." (ND .n. _U- O(D <.< .N-. [unreadable])s n'.< (-j Co- :.. -+. (1) a)> n[unreadable]33[unreadable]